DDR refers to a range of processes by which cells sense, signal and correct damage to genetic material. DNA damage has numerous sources such as chemotherapy, radiotherapy, UV light, replication errors and alkylating agents resulting in millions of lesions to the human genome every day. DNA repair processes continually keep the genome protected against the impact of propagating lesions that can have deleterious consequences. During tumourigenesis, genomic instability leads to mutations in key regulatory proteins including those involved in DDR/DNA repair, causing cells to become reliant on remaining DNA repair pathways. This reliance is known to vary between tumour types.
The concept of synthetic lethality was first derived from genetic studies in model organisms, where mutation of a particular gene results in lethality only through mutation or loss of another gene. The application of synthetic lethality to cancer biology has led to the discovery of novel therapeutic avenues to treat cancer. For instance, targeting DDR pathways that tumours have become reliant on has led to new approaches to selectively kill cancer cells with little toxicity to normal cells. In recent years, more rational approaches have been undertaken that are supported by the increased understanding of the type of pathways that are differentially defective in cancer versus normal cells (Nijman S M B and Friends S H, Science, 809-811).
The synthetic lethality approach to the treatment of cancer offers the possibility of selectively killing cancer cells by targeting pathways that the cell exclusively relies on for survival. This approach offers a significant advantage over cytotoxic chemotherapy and radiotherapy, and potentially represents a safer and more targeted treatment. However the characterisation of the specific dependencies based on this approach requires further understanding to enable the development of effective drugs useful in targeted cancer therapy.
The mouse USP4 orthologue was previously called the Unp gene. The USP4 gene maps to human chromosome 3p21.31. As ubiquitylation has been linked to regulation of cellular processes including protein homeostasis, transcription, and DNA repair, the inventors performed a cellular screen looking for synthetic lethality between USP4 and cell lines deficient in DDR proteins. They have identified that knockdown of USP4 resulted in synthetic lethality in cell lines depleted in DDR pathway proteins, particularly ATR, BRCA2, XRCC4 and Ligase IV. In addition, they found that depletion of USP4 was synthetic lethal in tumour cells resistant to treatment, such as cisplatin resistant cells compared to the parental control.